Family and twin studies have implicated a genetic contribution to the development of alcoholism. To identify these, we have focused on serotonergic behaviors, since alcoholism is associated with decreased serotonin turnover. The synthesis of serotonin, in raphe neurons, is governed tryptophan hydroxylase (TPH) enzyme activity. Since TPH is the rate-limiting enzyme in serotonin synthesis, we hypothesize that variants of TPH and factors controlling TPH gene expression, play a major role in serotonergic behaviors. We cloned and sequenced the cDNA and gene coding for murine TPH. This allowed the characterization of putative regualtory regions as well as its intron/exon structure. The murine TPH gene was mapped to chromosome & and the human TPH gene to chromosomal region 11p15.5. Polymorphic variants of the human, mouse and macaque TPH alleles were identified by SSCP analysis. The human TPH polymorphism associated with CSF 5-HIAA and blood glucose concentrations as well as suicidal behavior in implusive alcoholics. The mouse TPH polymorphism accounted for 6% of the variance in alcohol induced sleep time in recombinant inbred LS X SS mice. The TPH genotypes in the macaques are under investigation. These polymorphic alleles are being tested for their effect on TPH gene expression. Various drugs are being tested for their effect on TPH gene expression. DNA constructions were made, that are being assayed in tissue-specific and drug-activated and repressed TPH gene expression. Studies are under way to DNase I footprint transcription factor binding sites in the serotonergic behaviors by understanding natural genetic variants as well as determining the DNA sequences and factors required for TPH gene expression.